EP2744331A1 - Verfahren und zwischenprodukte zur herstellung von makrolactamen - Google Patents

Verfahren und zwischenprodukte zur herstellung von makrolactamen

Info

Publication number
EP2744331A1
EP2744331A1 EP12825726.8A EP12825726A EP2744331A1 EP 2744331 A1 EP2744331 A1 EP 2744331A1 EP 12825726 A EP12825726 A EP 12825726A EP 2744331 A1 EP2744331 A1 EP 2744331A1
Authority
EP
European Patent Office
Prior art keywords
compound
solution
compounds
added
hcv
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12825726.8A
Other languages
English (en)
French (fr)
Other versions
EP2744331A4 (de
Inventor
Nobuyoshi Yasuda
Jeffrey T. KUETHE
Guy Humphrey
Gregory L. Beutner
Yong-Li Zhong
Edward Cleator
Carl BAXTER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
Original Assignee
Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck Sharp and Dohme Ltd, Merck Sharp and Dohme LLC filed Critical Merck Sharp and Dohme Ltd
Publication of EP2744331A1 publication Critical patent/EP2744331A1/de
Publication of EP2744331A4 publication Critical patent/EP2744331A4/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
    • C07C35/04—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a three or four-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/32—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C271/34—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/013—Esters of alcohols having the esterified hydroxy group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/16—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • C07K5/126—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to process and intermediates that can be used for preparing macrolactams.
  • One use of the methods and intermediates described herein is the production of macrolactam compounds able to inhibit HCV NS3 protease activity.
  • HCV NS3 inhibitory compounds have therapeutic and research applications. BACKGROUND OF THE INVENTION
  • HCV infection is a major health problem. HCV infection leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals.
  • NS3 metalloprotease
  • NS3 serine protease
  • NS3 a helicase
  • NS5B RNA- dependent RNA polymerase
  • the NS3 protease is located in the N-terminal domain of the NS3 protein.
  • NS4A provides a cofactor for NS3 activity.
  • HCV protease activity include: Harper et al, WO2010011566; Liverton et al, WO2009134624;
  • the present invention includes methods and intermediates for preparing macrolactams.
  • One use of the methods and intermediates described herein is in the production of macrolactam compounds able to inhibit HCV NS3 protease activity.
  • HCV NS3 inhibitory compounds have therapeutic and research applications.
  • HCV inhibitory compound that can be produced using the method and intermediates described herein is Compound A, or a pharmaceutically salt thereof:
  • a first aspect of the present invention describes a compound selected from group consisting of: , or C(0)NHCH(X)COOH; provided that X is a C 2 -C 6 alkyl, or a C3-C8 cycloalkyl and R is a Ci_ 6 alkyl or aryl,
  • Compounds 6 are 7 are provided in a trans configuration.
  • Additional embodiments include methods for producing Compound 6.
  • Another aspect of the present invention describes a method of making a compound of: wherein R is C(0)NHCH(X)COOH, comprising the step of:
  • Compound 8 wherein X is a C 2 -C6 alkyl, or a C3-C8 cycloalkyl. Additional embodiments include methods of making Compound 7.
  • Another aspect of the present invention describes a method of producing Compound 13, comprising the step of:
  • Additional embodiments include methods for producing Compound 11.
  • PG refers to a protecting group.
  • Another aspect of the present invention describes a method for making mpound 14 comprising the step of coupling Compounds 13 and 8:
  • Additional embodiments include forming a macrolactam, adding functional groups; and producing Compound 13 and/or Compound 8 used in this aspect, by using methods described herein.
  • a preferred macrolactam compound produced using methods described herein is Compound A.
  • Figure 1 illustrates an X-ray diffraction pattern of a crystalline Compound 17.
  • Figure 2 illustrates an X-ray diffraction pattern of a crystalline Compound 18.
  • Compound A has the following structure:
  • Functional groups that can be modified include a different heterocycle group, a different alkyl in place of the t-butyl group, and alteration of the cyclopropylsulfonyl functional group (e.g., with an ethyl group replacing the ethylene and/or a methylcyclopropyl group replacing the cyclopropyl group).
  • Harper et al, WO2010011566 describes an alternative method for making Compound A. Harper et a/.,WO2010011566 et al, also includes data illustrating the ability of Compound A to inhibit HCV replicon activity and NS3/4A.
  • Macrolactam compounds able to inhibit HCV activity have different uses including inhibiting HCV activity in vivo, inhibiting HCV activity in vitro, and inhibiting HCV NS3 enzymatic activity. In vivo inhibition of HCV activity can be used for therapeutic applications. Inhibiting HCV activity in vitro has different applications including being used to obtain HCV resistant mutants, further characterizing the ability of a functional group to inhibit HCV replicon or enzymatic activity, and studying HCV replication or protease activity. Cyclopropyl Linker Synthesis
  • Scheme A illustrates an overall scheme for producing a cyclopropyl linker and different intermediates. Individual steps in Scheme A provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step.
  • LG refers to leaving group
  • Advantages of performing the different steps illustrated in Scheme A compared with a method of producing an alternative cyclopropyl linker having an ethylene group, described in Harper et al, WO 2010/011566, include: acetylide addition to the alkyl chloride having cyclopropane function to avoid forming double cyclopropanation, selective production of chiral intermediate (Compound 7), direct carbamate formation (which does not require protection), very high trans selectivity, avoiding the use of unstable enol silyl ether, and improved yield.
  • Compound 8 can be used, for example, as illustrated in Scheme C infra., to produce a macrolactam.
  • An as ect of the present invention is directed to a compound of Formula I: or salt thereof; wherein R is either H, C(0)R A , or C(0)NHCH(X)COOH; provided that X is a C 2 -C 6 alkyl, or a C3-C8 cycloalkyl and R A is a Ci_ 6 alkyl or aryl. Variations in the X group can be used to provide modifications to Compound A.
  • R is H; R is acetyl; R is C(0)NHCH(X)COOH and X is t-butyl; R is C(0)NHCH(X)COOH and X is cyclohexyl; or R is C(0)NHCH(X)COOH and X is cyclopentyl.
  • a compound of Formula I is present in a composition or mixture substantially free of its stereoisomers.
  • the percent of the ee form of Formula I present, with respect to other stereoisomers is at least 90% ee, at least 95%> ee, at least 90% to about 98% ee, or at least 95% to about 98% ee.
  • R is H and the ee form of the compound, with respect to other stereoisomers, is at least 90% ee, at least 95% ee, at least 90% to about 98% ee, or at least 95% to about 98% ee; R is
  • C(0)NHCH(X)COOH and the ee form of the compound, with respect to other stereoisomers is at least 90%> ee, at least 95%> ee, at least 90%> to about 98%> ee, or at least 95%> to about 98%> ee; and R is C(0)NHCH(X)COOH and X is either t-butyl, cyclopentyl or cyclohexyl, preferably t- butyl, and the ee form of the compound, with respect to other stereoisomers, is at least 90%> ee, at least 95% ee, at least 90% to about 98% ee, or at least 95% to about 98% ee.
  • Another aspect is directed to a method of producing a Formula I compound involving the enz matic resolution of Compound 6 to produce Compound 7:
  • Suitable enzymes are lipases or proteases, examples of which include Candida cylindraceae lipase 2, Pseudomonas cepacia lipase 2, Mucor miehei lipase, papain, Amano protease S (Bacillus stearothermophilus protease), Amano protease A (Aspergillus niger),
  • Protomax Novo, Enzyme Development Corp protese S20059, and Novozymes 435 (immobilized Candida antarctica lipase B).
  • the protease from Bacillus stearothermophilus and Novozymes 435 are preferred, and Novozymes 435 is most preferred.
  • the particular reaction conditions will vary depending upon the selected enzyme.
  • the enzyme is Novozyme 435 added to a buffer saturated organic solvent solution of Compound 6 at a temperature between 0 and 50°C .
  • Preferred reaction conditions are when the solvent is MTBE saturated with a 0.1 M K 2 HP0 4 solution and the reaction temperature is 10°C.
  • X is either t-butyl, cyclopentyl or cyclohexyl.
  • the reaction can be carried using a condensation reagent, optionally in the presence of base.
  • condensation reagents including CDI, phosgene, diphosgene, triphogene, and chlorocarbonates.
  • CDI is a preferred reagent.
  • the reaction is carried out in the presence of base.
  • suitable bases include typical bases and organic bases such as TEA, DIPEA, DABCO, and DBU.
  • TEA and DIPEA are preferred reagents for this reaction.
  • Compound 6 is produced from Compound 5 using an acetylating agent:
  • acetylating agents include acetyl chloride, acetyl bromide and acetic anhydride.
  • Suitable reaction conditions include the use of an aprotic organic solvent at a temperature between 0 and 50 °C followed by the addition of neutral aqueous solution and separation of the organic layer to obtain Compound 6.
  • Compound 5 is produced by mixing Compound 4 with a metal acetylide
  • the reaction can be carried out, for example, by mixing Compound 4 in with an organometallic reagent, in an aprotic organic solvent at a temperature between -78 and 30 °C. Mixing this solution with a polar aprotic solvent and a metallated acetylene at a temperature from 0-60°C followed by addition of an acidic aqueous solution and separation of the organic layer to obtain Compound 5.
  • organometallic reagents include alkyl lithiums, alkyl magnesium halides, sodium and potassium hydride.
  • polar aprotic solvents include, DMSO, DMF, N,N-dimethylacetamide, N-methyl pyrrolidinone, hexamethylphosphoramide and DMPU.
  • metallated acetylene such as lithium acetylide-ethylene diamine complex or potassium acetylide is used, at a temperature from 0-60 °C followed by addition of an acidic aqueous solution and separation of the organic layer to obtain Compound 5.
  • Compound 4 is produced by oxidizing Compound 3.
  • the reaction can be carried out by mixing Compound 3 with an oxidant in a protic or aprotic organic solvent at a temperature between 0 and 100 °C.
  • oxidants include hydrogen peroxide, alkyl hydrogen peroxides, sodium perborate, and sodium and potassium persulfate.
  • Compound 3 is produced from Compound 2:
  • the reaction can be performed, for example, by mixing Compound 2 with an alkyl zinc reagent, an acid, and a dihalomethane in a halogenated solvent at a temperature between 0 and 40 °C followed by addition of an acidic aqueous solution and separation of the organic layer to obtain Compound 3.
  • suitable acids include alkyl and aryl carboxylic acids, sulfonic acids or phosphoric acids.
  • Compound 2 can be prepared as described by Shirakawa et al. Synthesis 77: 1814-
  • Scheme B illustrates a scheme for producing a quinoloxine and joining it to a hydroxyproline. Individual steps in Scheme B provide for additional embodiments. Further embodiments include steps upstream and downstream from a particular step. Alternative heterocycles can be joined to hydroxyproline using the provided procedures.
  • 2010/011566 include eliminating a poor selective chloration intermediate, and eliminating four steps by allowing for the use of natural hydroxyproline.
  • Another aspect of the present invention is directed to production of Compound
  • the reaction can be carried out by SnAr replacement of Compound 11 with
  • a general temperature for the reaction is 20-100 °C, with a preferred temperature being -50 °C.
  • a wide range of solvents can be using including aprotic polar solvents, DMF, DM Ac, NMP, DMSO, and DMPU.
  • a preferred solvent is DM Ac.
  • Different bases can be used including CS 2 CO 3 , DBU, K 2 CO 3 , K 3 PO 4 , and KOtBu.
  • a preferred base is DBU.
  • Compound 11 is produced by:
  • Com ound 10 is produced by:
  • Preferred reaction conditions providing advantages compared with an alternative method described in Harper et ah, WO 2010/011566 include: use of the highly effective Sonogashira/Macrolactamization method in forming Compound 14, from Compounds 8 and 13; a one-pot procedure going from Compound 14 to 15 to 16 to 17; and producing Compound A from Compounds 18 and 19 using EDC instead of HATU.
  • Compounds 18 and 19 can be carried out using pyridine or a pyridine derivatives, where HOBt is either not present or is present in very small amounts.
  • HOBt is either not present or is present in very small amounts.
  • the use of pyridine or a pyridine derivative instead of HOBt for coupling offers several advantages including higher yield and less emerization on the proline a-center.
  • HOBt is shock sensitive in a dry state.
  • An aspect of the present invention is directed to a compound selected from the consisting of:
  • Another aspect of the present invention is directed to the production of
  • a first embodiment involves Sonogashira cross coupling of Compounds 13 and 8 in the presence of tri tert-butylphosphine tetrafluoroborate salt in a solvent system.
  • a preferred general temperature range is -50-100 °C, more preferable the temperature is about 80 °C.
  • suitable solvent systems include CPME and MeCN, THF, 2-MeTHF, toluene CPME alone and MeCN alone.
  • a preferred solvent system is CPME and MeCN.
  • suitable catalysts include Pd and copper.
  • a preferred catalyst is Pd(OAc) 2 .
  • salts of Compound 8 are directly employed in the Sonogashira cross coupling reaction with Compound 13 to give Compound 14.
  • This reaction can be carried out in the presence of tri fert-butylphosphine tetrafluoroborate salt in a solvent.
  • the preferred solvent for this transformation is DMF.
  • a preferred general temperature range is ⁇ 40- 80 °C, more preferable the temperature is about 65 °C, and the preferred catalyst is Pd(OAc) 2 .
  • Examples of salt that can employed include dibenzylamine and t-butylamine.
  • Suitable conditions include the use of a palladium catalyst and solvent.
  • solvents include EtOAc, MeOH, and IPAc/MeOH mixture.
  • IPAc/MeOH mixture is a preferred solvent.
  • a general temperature range is 0 to 35 °C, preferably 15-20 °C.
  • any of Compounds 15 and 16 can be provided as salts.
  • Suitable conditions are a range of acids and solvents. Examples of acids are methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, trifluoroacetic acid, hydrochloric acid, phosphoric acid, and
  • solvents examples include THF, iPrOAc, MeCN, and CH 2 C1 2 .
  • the second and third embodiments are performed in a one- pot procedure for the protection/macrolactamization/isolation to provide a crystal of Compound 17.
  • Compound A is produced by coupling Compound 18 with
  • General coupling (condensation) reagents can be employed.
  • the reaction can be done under standard coupling conditions with typically carbodiimide type of reagents, such as DCC, EDC, etc and in the presence or absence of HOBt, HOPO, or pyridine derivative etc.
  • An example of suitable conditions includes using a carbodiimide, an activator and a tertiary organic base in a polar aprotic solvent at a temperature between 0 and 40°C.
  • activators include HOBt and HO AT.
  • about 1.2 equiv EDC about 2.4 equiv HOBt- 3 ⁇ 40, and about 2.4 equiv of DIPEA in about 5 volumes DMF are employed.
  • Compound A is produced by coupling Compound 18 with Compound 19 using pyridine or a pyridine derivative.
  • the reaction can be carried out using a coupling reagent, an aprotic organic solvent and pyridine or a pyridine derivative.
  • a general temperature is 0 °C to 50 °C (preferably room temperature).
  • Examples of coupling reagents include dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '- diisopropylcarbodiimide (DIC), and l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).
  • Examples of aprotic organic solvents include acetonitrile, THF, and toluene. In an embodiment EDC is used. In an embodiment, at least 10 equivalents of pyridine are used with acetonitrile.
  • Preferred pyridine derivatives have electron donating or neutral groups at the 3 and 4 position. Exam les of general structures covering pyridine and derivatives include:
  • R 5 is either hydrogen, aryl, halogen, Cl-6 alkyl, O-Cl-6 alkyl or C3-C8 cycloalkyl.
  • Preferred reagents are pyridine, 4-phenylpyridine, 4-alkylpyridine, methylpyridine,
  • alkyl refers to a monovalent straight or branched chain, saturated aliphatic hydrocarbon radical having a number of carbon atoms in the specified range.
  • Cl-6 alkyl refers to any of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t-butyl, n- and iso- propyl, ethyl, and methyl.
  • Cl-4 alkyl refers to n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl, and methyl.
  • cycloalkyl refers to any monocyclic ring of an alkane having a number of carbon atoms in the specified range.
  • C3-8 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).
  • haloalkyl refers to an alkyl group as defined above in which one or more of the hydrogen atoms have been replaced with a halogen (i.e., F, CI, Br and/or I).
  • a halogen i.e., F, CI, Br and/or I.
  • Cl-6 haloalkyl or “C1-C6 haloalkyl” refers to a Cl to C6 linear or branched alkyl group as defined above with one or more halogen substituents.
  • fluoroalkyl has an analogous meaning except the halogen substituents are restricted to fluoro. Suitable fluoroalkyls include the series (CH2)0-4CF3 (i.e., trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoro-n-propyl, etc.).
  • PG indicates a protecting group. In different embodiments described throughout the application where a protecting group is employed: PG is either BOC or Fmoc; or PG is BOC.
  • aryl is either phenyl, substituted phenyl, naphthyl, substituted naphthyl, heteroaryl, or substituted heteroaryl, provided that substituted phenyl, substituted naphthyl, and substituted heteroaryl, each have 1 to 5 substituents independently selected from the group consisting of:
  • Cl-6 alkyl (2) C 1 -6 alkyl substituted with OH, O-C 1 -6 alkyl, O-C 1 -6 haloalkyl, CN, N02, N(RC)RD C(0)N(RC)RD C(0)RC, C02R C , SRC, S(0)RC, SO2RC, S02N(RC)RD ? N(RC)C(0)RD, N(RC)C02R°, N(RC)S02R D , N(RC)S02N(RC)RD OC(0)N(RC)RD ? N(RC)C(0)N(RC)RD ? or
  • R ⁇ and R" are each independently H or Ci_ 6 alkyl.
  • heteroaryl is a (i) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S or (ii) a 9- or 10-membered bicyclic, fused ring system containing from 1 to 4 heteroatoms independently selected from N, O and S.
  • the atoms in a compound described herein may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of described herein.
  • different isotopic forms of hydrogen (H) include protium (IK) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds described herein can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples provided herein using appropriate isotopically-enriched reagents and/or intermediates.
  • CDI 1 , 1 '-Carbonyldiimidazole
  • DIPEA Diisopropylethylamine
  • HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophoshate
  • IP Ac Isopropyl acetate
  • compositions for treating patients can be used with compounds for treating patients.
  • Non-pharmaceutical salts may, however, be useful in the preparation of intermediate compounds.
  • Pharmaceutically acceptable salts are suitable for administration to a patient, preferably, a human.
  • Suitable salts include acid addition salts which may, for example, be formed by mixing a solution of a compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, or benzoic acid.
  • Compounds carrying an acidic moiety can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands such as quaternary ammonium salts.
  • suitable organic ligands such as quaternary ammonium salts.
  • pharmaceutically acceptable esters can be employed to modify the solubility or hydrolysis characteristics of the compound.
  • compositions described herein having therapeutic applications can be administered to a patient infected with HCV.
  • administration and variants thereof (e.g., “administering” a compound) means providing the compound to the individual in need of treatment.
  • administration and its variants are each understood to include concurrent and sequential provision of the compound or salt and other agents.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product which results, directly or indirectly, from combining the specified ingredients.
  • pharmaceutically acceptable is meant the ingredients of the pharmaceutical composition must be compatible with each other and are suitable to the recipient thereof.
  • subject refers to an animal, preferably a mammal, most preferably a human, who is the object of treatment, observation or experiment.
  • an effective amount indicates a sufficient amount to exert a therapeutic or prophylactic effect.
  • an effective amount is sufficient to achieve one or more of the following effects: reduce the ability of HCV to replicate, reduce HCV load, and increase viral clearance.
  • an effective amount is sufficient to achieve one or more of the following: a reduced susceptibility to HCV infection, and a reduced ability of the infecting virus to establish persistent infection for chronic disease.
  • the compounds can be administered by means that produces contact of the active agent with the agent's site of action. They can be administered by conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but typically are
  • a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • Compounds can, for example, be administered by one or more of the following routes: orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation (such as in a spray form), or rectally, in the form of a unit dosage of a pharmaceutical composition containing an effective amount of the compound and pharmaceutically-acceptable carriers (e.g., a carrier suitable for administration to a human patient), adjuvants and vehicles.
  • pharmaceutically-acceptable carriers e.g., a carrier suitable for administration to a human patient
  • Liquid preparations suitable for oral administration e.g., suspensions, syrups, elixirs and the like
  • media such as water, glycols, oils, alcohols and the like.
  • Solid preparations suitable for oral administration can be prepared according to techniques known in the art and can employ solid excipients as such starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like.
  • Parenteral compositions can be prepared according to techniques known in the art and typically employ sterile water as a carrier and optionally other ingredients, such as solubility aids.
  • injectable solutions can be prepared according to methods known in the art wherein the carrier comprises a saline solution, a glucose solution or a solution containing a mixture of saline and glucose.
  • Therapeutic compounds can be administered orally in a dosage range of 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in a single dose or in divided doses.
  • mammal e.g., human
  • One dosage range is 0.01 to 500 mg/kg body weight per day orally in a single dose or in divided doses.
  • Another dosage range is 0.1 to 100 mg/kg body weight per day orally in single or divided doses.
  • the compositions can be provided in the form of tablets or capsules containing 1.0 to 500 mg of the active ingredient, particularly 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, and 750 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • HCV NS3 activity HCV replicon activity
  • HCV replication activity can be evaluated using techniques well-known in the art. (See, for example, Carroll et al., J. Biol. Chem. 275: 11979-11984, 2003.)
  • TRF time-resolved fluorescence
  • a NS3 protease assay can be performed, for example, in a final volume of 100 ⁇ assay buffer containing 50 mM HEPES, pH 7.5, 150 mM NaCl, 15 % glycerol, 0.15 % TRITON X-100, 10 mM DTT, and 0.1 % PEG 8000.
  • NS3 and NS4A are pre-incubated with various concentrations of inhibitors in DMSO for 30 minutes. The reaction is initiated by adding the TRF peptide substrate (final concentration 100 nM).
  • NS3 mediated hydrolysis of the substrate is quenched after 1 hour at room temperature with 100 ⁇ of 500 mM MES, pH 5.5.
  • Product fluorescence is detected using either a VICTOR V2 or FUSION fluorophotometer (Perkin Elmer Life and Analytical Sciences) with excitation at 340 nm and emission at 615 nm with a 400 delay. Testing concentrations of different enzyme forms are selected to result in a signal to background ratio (S/B) of 10-30.
  • S/B signal to background ratio
  • IC 50 values are derived using a standard four- parameter fit to the data. K; values are derived from IC 50 values using the following formula,
  • reaction mixture was diluted with 200 mL of water.
  • the biphasic mixture was transferred to a separatory funnel and the aqueous layer removed.
  • the organic layer was washed with 200 mL of 2 N HCl and then with 300 mL of sat. NaHC0 3 prior to drying over MgSC ⁇ .
  • the solvent was removed in vacuo to give 41.8 g of rac-6 (>99% yield).
  • the mixture was aged for 30 min to dissolve all the solids and then transferred to a 100 L cylindrical extractor.
  • the aqueous layer was then washed with 12 L of MTBE.
  • the bottom aqueous layer was drained and the top MTBE layer was discarded.
  • the aqueous layer was washed with 8 L of MTBE.
  • the bottom aqueous layer was drained and the top MTBE layer was discarded.
  • the MTBE layer was then transferred via vacuum into a 50 L round bottom flask equipped with a mechanical stirrer, thermocouple, and batch concentrator and the solvent was removed under reduced pressure keeping the internal temperature of the batch ⁇ 20 °C during the distillation.
  • the solvent was then switched to cyclopentyl methyl ether (CPME) by flushing with ⁇ 5 L of CPME and then diluted to a final volume of ⁇ 20 L. This material was used in the next reaction without further purification.
  • CPME cyclopentyl methyl ether
  • the resulting grey slurry was then cooled to an internal temperature of 20 °C overnight
  • the slurry was filtered, water (1.0-1.5 L/Kg) was used to help with the transfer.
  • the light grey solids were washed with 2 cake volumes water (5.0-5.5 L/Kg).
  • the solids were dried under vacuum/N 2 sweep for 24 hours, at which time the solids were still very wet.
  • thermocouple and condenser was added to Compound 10 (3.8 kg), and charged slowly at room temperature with POCI 3 (5.92 L @ 99%). There was no initial temperature change. The grey slurry was heated to 98 °C for 20 hours. After 2-3 hours the slurry turned from grey to green, then to yellow and finally turned homogeneous red. As the slurry became homogenous in POCI 3 , significant amounts of HC1 off-gassing were produced. The reaction was monitored by HPLC. The dark red, homogenous solution was allowed to cool slowly to below 80 °C.
  • the reaction mixture was concentrated and azotroped by MTBE until the KF of the solution was ⁇ 300 ppm, and adjusted to a total volume (18 L).
  • the solution was seeded, and stirred at room temperature for 5 hours.
  • Heptane (21.5 L) was slowly added over 2 hours.
  • the resulting slurry was stirred at room temperature overnight, and at 5-10 °C for 2 hours.
  • the crystalline solid was collected by filtration, washed with cold heptane/MTBE (3 : 1 , 16 L), heptane (10 L), and dried under vacuum with nitrogen sweep to afford desired product Compound 13 (5.68 kg, 96.7 A%, 95.5 wt%, 71% isolated yield after correction), m.p. 98.5-99 °C.
  • Retention time for regioisomer 4.927 min.
  • the reaction mixture was filtered through Solka floe eluting with IP Ac. The filtrate was then concentrated under reduced pressure in a 100 mL round bottom flask equipped with a thermocouple, mechanical stirrer, and batch concentrator. The solvent was switched to MeCN and a final volume of ⁇ 50 mL. Final assay of the combined batches was 7.25 g (89%) of the product Compound 15. The crude product was used without further purification in the next step.
  • HPLC Conditions Zorbax Eclipse Plus C18 50 x 4.6 mm, 1.8 um, 1.5 mL/min, 230 nm, 25 °C, Eluents: Water 0.1% H 3 P0 4 (A), Acetonitrile (B). 90% A 0 min, 5% A 5 min, 5% A 6 min.
  • the ethyl acetate/ THF solution was concentrated to 4 volumes (14 L) and then flushed with 18 L ethyl acetate keeping the volume constant at 14 L. To the slurry was added 38.5 L hexanes over 4 hours. The slurry was aged overnight at ambient temperature.
  • the Boc-sulfonamide was charged in a 75 L 4-neck round bottomed flask fitted with overhead stirrer, temperature probe, and N 2 inlet. Ethyl acetate (22.6 L) was added followed by the TsOH. The mixture was aged at ambient temperature for 23.5 hours The mixture is homogeneous at the start, but forms precipitates during the overnight age giving a free flowing white slurry.
  • Compound A was dissolved in acetone 4L at RT, filtered and transferred to a 12 L RBF with overhead stirring, rinsed with extra acetone 1L, heated to 50 °C, water 0.9L was added, seeded lOg, aged 15minutes, then added water 0.8L over 2.5 hours, extra water 3.3v over 2.5 hours was added, stopped heating, cooled to RT, aged at RT overnight, filtered, washed with water/acetone (1 : 1 v/v) 4L, and dried in air under vacuum.
  • Compound A Hydrate III, 670 g was obtained as an off-white solid.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Oncology (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Cephalosporin Compounds (AREA)
EP12825726.8A 2011-08-19 2012-08-16 Verfahren und zwischenprodukte zur herstellung von makrolactamen Withdrawn EP2744331A4 (de)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161525462P 2011-08-19 2011-08-19
US201161533439P 2011-09-12 2011-09-12
US201161533915P 2011-09-13 2011-09-13
US201161539540P 2011-09-27 2011-09-27
PCT/US2012/051182 WO2013028471A1 (en) 2011-08-19 2012-08-16 Methods and intermediates for preparing macrolactams

Publications (2)

Publication Number Publication Date
EP2744331A1 true EP2744331A1 (de) 2014-06-25
EP2744331A4 EP2744331A4 (de) 2015-01-21

Family

ID=47746773

Family Applications (3)

Application Number Title Priority Date Filing Date
EP12825540.3A Withdrawn EP2744507A4 (de) 2011-08-19 2012-08-16 Kristallformen eines hcv-proteasehemmers
EP12826404.1A Not-in-force EP2744336B1 (de) 2011-08-19 2012-08-16 Verfahren und zwischenprodukte zur herstellung von makrolactamen
EP12825726.8A Withdrawn EP2744331A4 (de) 2011-08-19 2012-08-16 Verfahren und zwischenprodukte zur herstellung von makrolactamen

Family Applications Before (2)

Application Number Title Priority Date Filing Date
EP12825540.3A Withdrawn EP2744507A4 (de) 2011-08-19 2012-08-16 Kristallformen eines hcv-proteasehemmers
EP12826404.1A Not-in-force EP2744336B1 (de) 2011-08-19 2012-08-16 Verfahren und zwischenprodukte zur herstellung von makrolactamen

Country Status (11)

Country Link
US (3) US9238604B2 (de)
EP (3) EP2744507A4 (de)
JP (2) JP2014521750A (de)
KR (2) KR20140053330A (de)
CN (2) CN103874414A (de)
AU (2) AU2012299218A1 (de)
BR (2) BR112014003798A2 (de)
CA (2) CA2844388A1 (de)
MX (2) MX2014001944A (de)
RU (2) RU2014110399A (de)
WO (3) WO2013028465A1 (de)

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CA2844388A1 (en) 2011-08-19 2013-02-28 Merck Sharp & Dohme Corp. Process and intermediates for preparing macrolactams
UA119315C2 (uk) 2012-07-03 2019-06-10 Гіліад Фармассет Елелсі Інгібітори вірусу гепатиту с
ES2613766T3 (es) 2012-10-19 2017-05-25 Bristol-Myers Squibb Company Derivados de carbamato de hexadecahidrociclopropa(e)pirrolo(1,2-a)(1,4)diazaciclopentadecinilo sustituidos con 9-metilo como inhibidores de la proteasa no estructural 3 (NS3) para el tratamiento de infecciones del virus de la hepatitis C
US9334279B2 (en) 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9598433B2 (en) 2012-11-02 2017-03-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
WO2014070974A1 (en) 2012-11-05 2014-05-08 Bristol-Myers Squibb Company Hepatitis c virus inhibitors
EP2764866A1 (de) 2013-02-07 2014-08-13 IP Gesellschaft für Management mbH Hemmer der nedd8-aktivierenden Enzyme
JP6342922B2 (ja) 2013-03-07 2018-06-13 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｃ型肝炎ウイルス阻害剤
AU2014233390B2 (en) 2013-03-15 2018-03-01 Gilead Sciences, Inc. Macrocyclic and bicyclic inhibitors of hepatitis C virus
SG11201602693QA (en) 2013-10-18 2016-05-30 Merck Sharp & Dohme Methods and intermediates for preparing macrolactams
WO2015095437A1 (en) * 2013-12-20 2015-06-25 Merck Sharp & Dohme Corp. Methods and intermediates for the preparation of macrolactams
EP3572416B1 (de) 2014-01-24 2022-09-21 Turning Point Therapeutics, Inc. Diaryl-makrocyclen als modulatoren von proteinkinasen
US9321807B2 (en) 2014-06-06 2016-04-26 Abbvie Inc. Crystal forms
RU2732405C2 (ru) 2015-07-02 2020-09-16 Тёрнинг Поинт Терапьютикс, Инк. Хиральные диарильные макроциклы в качестве модуляторов протеинкиназ
LT3319969T (lt) * 2015-07-06 2024-06-10 Turning Point Therapeutics, Inc. Diarilo makrociklo polimorfas
AU2016296878B2 (en) * 2015-07-21 2020-12-17 Turning Point Therapeutics, Inc. Chiral diaryl macrocycles and uses thereof
WO2017197046A1 (en) 2016-05-10 2017-11-16 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
EP3454862A4 (de) 2016-05-10 2020-02-12 C4 Therapeutics, Inc. Spirocyclische degronimere für zielproteinabbau
CN109562107A (zh) 2016-05-10 2019-04-02 C4医药公司 用于靶蛋白降解的杂环降解决定子体
SG11201900163PA (en) 2016-07-28 2019-02-27 Tp Therapeutics Inc Macrocycle kinase inhibitors
TWI808958B (zh) 2017-01-25 2023-07-21 美商特普醫葯公司 涉及二芳基巨環化合物之組合療法
UA126158C2 (uk) 2017-07-28 2022-08-25 Тьорнінґ Поінт Терапьютикс, Інк. Макроциклічні сполуки і їх використання
EP3728271B1 (de) 2017-12-19 2022-09-28 Turning Point Therapeutics, Inc. Makrocyclische verbindungen zur behandlung von krankheiten
CN111057045A (zh) * 2019-12-18 2020-04-24 安徽红杉生物医药科技有限公司 Hcv ns3/4a蛋白酶抑制剂中间体及其合成方法、应用
CN112174982A (zh) * 2020-09-10 2021-01-05 上海希迈医药科技有限公司 一种洛普替尼晶型及其制备方法

Family Cites Families (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4871868A (en) 1987-03-11 1989-10-03 Takeda Chemical Industries, Ltd. Production of substituted acetylenic compounds
GB9207987D0 (en) 1992-04-10 1992-05-27 Smithkline Beecham Plc Novel container and closure
US5716960A (en) * 1995-01-13 1998-02-10 U.S. Bioscience Inc. And Individuals Crystalline trimetrexate salts and the process for making the same
ZA98879B (en) * 1997-02-04 1998-08-03 Ono Pharmaceutical Co Omega-cycloalkyl-prostaglandin e2 derivatives
NO317155B1 (no) 1997-02-04 2004-08-30 Ono Pharmaceutical Co <omega>-cykloalkyl-prostagladin-E<N>2</N>-derivater
WO2006088129A1 (ja) 2005-02-18 2006-08-24 Mitsubishi Pharma Corporation プロリン誘導体の塩、またはその溶媒和物、及びその製造方法
US7834145B2 (en) 2005-03-22 2010-11-16 Merck Sharp & Dohme Corp. HCV protease substrates
AU2006242475B2 (en) 2005-05-02 2011-07-07 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
AR057456A1 (es) 2005-07-20 2007-12-05 Merck & Co Inc Inhibidores de la proteasa ns3 del vhc
UA90909C2 (en) * 2005-07-20 2010-06-10 Мерк Шарп Энд Домэ Корп. Hcv ns3 protease inhibitors
MX2008001588A (es) 2005-08-01 2008-02-19 Merck & Co Inc Inhibidores de proteasa ns3 del vhc.
EP2018146A2 (de) 2006-03-07 2009-01-28 The Procter and Gamble Company Zusammensetzungen zur oxidativen färbung von keratinfasern und verfahren zur verwendung dieser zusammensetzungen
GB0609492D0 (en) 2006-05-15 2006-06-21 Angeletti P Ist Richerche Bio Therapeutic agents
GB0612423D0 (en) 2006-06-23 2006-08-02 Angeletti P Ist Richerche Bio Therapeutic agents
CA2667266C (en) 2006-10-24 2015-11-24 Merck & Co., Inc. Hcv ns3 protease inhibitors
WO2008051477A2 (en) 2006-10-24 2008-05-02 Merck & Co., Inc. Hcv ns3 protease inhibitors
EP2086982B1 (de) 2006-10-27 2018-08-29 Merck Sharp & Dohme Corp. Hcv-ns3-protease-hemmer
WO2008057208A2 (en) 2006-10-27 2008-05-15 Merck & Co., Inc. Hcv ns3 protease inhibitors
CA2686138A1 (en) 2007-05-03 2008-11-13 Intermune, Inc. Novel macrocyclic inhibitors of hepatitis c virus replication
US8927569B2 (en) 2007-07-19 2015-01-06 Merck Sharp & Dohme Corp. Macrocyclic compounds as antiviral agents
US8591878B2 (en) 2008-02-25 2013-11-26 Merck Sharp & Dohme Corp. Therapeutic compounds
CA2722326A1 (en) * 2008-04-24 2009-10-29 Incyte Corporation Macrocyclic compounds and their use as kinase inhibitors
WO2009131196A1 (ja) * 2008-04-24 2009-10-29 武田薬品工業株式会社 置換ピロリジン誘導体およびその用途
US8461107B2 (en) 2008-04-28 2013-06-11 Merck Sharp & Dohme Corp. HCV NS3 protease inhibitors
SI2540350T1 (sl) 2008-07-22 2015-01-30 Merck Sharp & Dohme Corp. Kombinacije makrocikliäśnih kinoksalinske spojine, ki je hcv ns3 proteazni inhibitor z drugimi hcv uäśinkovinami
US8828930B2 (en) 2009-07-30 2014-09-09 Merck Sharp & Dohme Corp. Hepatitis C virus NS3 protease inhibitors
JP5789260B2 (ja) * 2009-08-27 2015-10-07 メルク・シャープ・エンド・ドーム・コーポレイション Ｃ型肝炎ウイルスのプロテアーゼ阻害薬の調製方法
CA2844388A1 (en) 2011-08-19 2013-02-28 Merck Sharp & Dohme Corp. Process and intermediates for preparing macrolactams

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MONTSERRAT ARMENGOL ET AL.: "Synthesis of thieno[2,3b]quinoxalines from 2-haloquinoxalines", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANS., vol. 1, 19 December 2000 (2000-12-19), pages 154-158, XP002732625, *
SARGES R ET AL: "4-AMINOÚ1,2,4 3/4 TRIAZOLOÚ4,3-ALPHA 3/4 QUINOXALINES. A NOVEL CLASS OF POTENT ADENOSINE RECEPTOR ANTAGONISTS AND POTENTIAL RAPID-ONSET ANTIDEPRESSANTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 33, no. 8, 1 January 1990 (1990-01-01), pages 2240-2254, XP002915772, ISSN: 0022-2623, DOI: 10.1021/JM00170A031 *
See also references of WO2013028471A1 *

Also Published As

Publication number Publication date
JP2014524442A (ja) 2014-09-22
US9073825B2 (en) 2015-07-07
RU2014110399A (ru) 2015-09-27
US20140200343A1 (en) 2014-07-17
AU2012299218A1 (en) 2014-02-20
BR112014003802A2 (pt) 2017-06-13
KR20140053330A (ko) 2014-05-07
KR20140059236A (ko) 2014-05-15
BR112014003798A2 (pt) 2017-03-01
EP2744331A4 (de) 2015-01-21
MX2014001944A (es) 2014-03-27
US9242917B2 (en) 2016-01-26
RU2014110400A (ru) 2015-09-27
EP2744336A4 (de) 2014-12-31
MX2014001945A (es) 2014-03-27
WO2013028471A1 (en) 2013-02-28
EP2744336B1 (de) 2017-07-05
EP2744507A4 (de) 2015-01-28
WO2013028465A1 (en) 2013-02-28
CA2844386A1 (en) 2013-02-28
CN103889439A (zh) 2014-06-25
EP2744336A1 (de) 2014-06-25
JP2014521750A (ja) 2014-08-28
US20140243519A1 (en) 2014-08-28
WO2013028470A1 (en) 2013-02-28
US9238604B2 (en) 2016-01-19
EP2744507A1 (de) 2014-06-25
CN103874414A (zh) 2014-06-18
US20140206605A1 (en) 2014-07-24
CA2844388A1 (en) 2013-02-28
AU2012299223A1 (en) 2014-02-27

Similar Documents

Publication Publication Date Title
WO2013028471A1 (en) Methods and intermediates for preparing macrolactams
JP6034802B2 (ja) 大環状ラクタムの調製のための方法および中間体
CN111343990B (zh) 苯并二氮杂䓬-2-酮和苯并氮杂䓬-2-酮衍生物的拆分方法
TWI406660B (zh) Ｃ型肝炎病毒之巨環抑制劑
JP5021711B2 (ja) Ｃ型肝炎インヒビタートリペプチド
EP2079480A2 (de) Hcv-ns3 -proteasehemmer
WO2015095430A1 (en) Methods and intermediates for the preparation of macrolactams
RU2776703C2 (ru) Способы разделения производных бензодиазепин-2-она и бензоазепин-2-она
WO2015095437A1 (en) Methods and intermediates for the preparation of macrolactams

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140319

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/44 20060101ALI20141124BHEP

Ipc: A01N 43/04 20060101AFI20141124BHEP

Ipc: A01N 43/42 20060101ALI20141124BHEP

Ipc: A61K 31/70 20060101ALI20141124BHEP

A4 Supplementary search report drawn up and despatched

Effective date: 20141219

RIC1 Information provided on ipc code assigned before grant

Ipc: A01N 43/42 20060101ALI20141215BHEP

Ipc: A61K 31/44 20060101ALI20141215BHEP

Ipc: A01N 43/04 20060101AFI20141215BHEP

Ipc: A61K 31/70 20060101ALI20141215BHEP

17Q First examination report despatched

Effective date: 20150806

RIC1 Information provided on ipc code assigned before grant

Ipc: C07D 498/16 20060101AFI20160714BHEP

Ipc: C07K 5/078 20060101ALI20160714BHEP

Ipc: C07D 403/12 20060101ALI20160714BHEP

Ipc: C07C 35/04 20060101ALI20160714BHEP

Ipc: C07C 67/14 20060101ALI20160714BHEP

Ipc: C07C 271/34 20060101ALI20160714BHEP

Ipc: C07C 69/12 20060101ALI20160714BHEP

Ipc: C07C 269/04 20060101ALI20160714BHEP

Ipc: C07C 69/013 20060101ALI20160714BHEP

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

INTG Intention to grant announced

Effective date: 20160915

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20170126